Oxygen enhancing membrane systems for implantable devices

ABSTRACT

The present invention relates generally to systems and methods for increasing oxygen availability to implantable devices. The preferred embodiments provide a membrane system configured to provide protection of the device from the biological environment and/or a catalyst for enabling an enzymatic reaction, wherein the membrane system includes a polymer formed from a high oxygen soluble material. The high oxygen soluble polymer material is disposed adjacent to an oxygen-utilizing source on the implantable device so as to dynamically retain high oxygen availability to the oxygen-utilizing source during oxygen deficits. Membrane systems of the preferred embodiments are useful for implantable devices with oxygen-utilizing sources and/or that function in low oxygen environments, such as enzyme-based electrochemical sensors and cell transplantation devices.

INCORPORATION BY REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. This application is a continuation of U.S. application Ser.No. 13/187,277, filed Jul. 20, 2011, which is a continuation of U.S.application Ser. No. 11/410,392 filed Apr. 25, 2006, now U.S. Pat. No.8,255,033, which is a continuation of U.S. application Ser. No.10/896,639 filed Jul. 21, 2004, now U.S. Pat. No. 7,379,765, whichclaims the benefit of priority under 35 U.S.C. §119(e) to U.S.Provisional Application No. 60/490,009, filed Jul. 25, 2003. Each of theaforementioned applications is incorporated by reference herein in itsentirety, and each is hereby expressly made a part of thisspecification.

FIELD OF THE INVENTION

The present invention relates generally to systems and methods forincreasing oxygen availability in implantable devices.

BACKGROUND OF THE INVENTION

Electrochemical sensors are useful in chemistry and medicine todetermine the presence or concentration of a biological analyte. Suchsensors are useful, for example, to monitor glucose in diabetic patientsand lactate during critical care events.

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non-insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which causes an arrayof physiological derangements (kidney failure, skin ulcers, or bleedinginto the vitreous of the eye) associated with the deterioration of smallblood vessels. A hypoglycemic reaction (low blood sugar) is induced byan inadvertent overdose of insulin, or after a normal dose of insulin orglucose-lowering agent accompanied by extraordinary exercise orinsufficient food intake.

Conventionally, a diabetic person carries a self-monitoring bloodglucose (SMBG) monitor, which typically utilizes uncomfortable fingerpricking methods. Due to the lack of comfort and convenience, a diabeticnormally only measures his or her glucose level two to four times perday. Unfortunately, these time intervals are spread so far apart thatthe diabetic likely finds out too late, sometimes incurring dangerousside effects, of a hyperglycemic or hypoglycemic condition. In fact, itis not only unlikely that a diabetic will take a timely SMBG value, butadditionally the diabetic will not know if their blood glucose value isgoing up (higher) or down (lower) based on conventional methods.

Consequently, a variety of transdermal and implantable electrochemicalsensors are being developed for continuously detecting and/orquantifying blood glucose values. Many implantable glucose sensorssuffer from complications within the body and provide only short-term orless-than-accurate sensing of blood glucose. Similarly, transdermalsensors have problems in accurately sensing and reporting back glucosevalues continuously over extended periods of time. Some efforts havebeen made to obtain blood glucose data from implantable devices andretrospectively determine blood glucose trends for analysis; howeverthese efforts do not aid the diabetic in determining real-time bloodglucose information. Some efforts have also been made to obtain bloodglucose data from transdermal devices for prospective data analysis,however similar problems have been observed.

SUMMARY OF THE PREFERRED EMBODIMENTS

Sensors that can provide accurate, real-time information under ischemicconditions are therefore desirable.

Accordingly, in a first embodiment, an electrochemical sensor fordetermining a presence or a concentration of an analyte in a fluid isprovided, the sensor including a membrane system including an enzymedomain including an enzyme that reacts with the analyte in the fluid asit passes through the enzyme domain; and a working electrode including aconductive material, wherein the working electrode is configured tomeasure a product of a reaction of the enzyme with the analyte, whereinthe membrane system includes a polymer material with a high oxygensolubility.

In an aspect of the first embodiment, the enzyme domain includes apolymer material with a high oxygen solubility.

In an aspect of the first embodiment, the polymer material is selectedfrom the group consisting of silicone, fluorocarbon, andperfluorocarbon.

In an aspect of the first embodiment, the sensor further includes aresistance domain configured to restrict a flow of the analytetherethrough, wherein the resistance domain is located more distal tothe working electrode than the enzyme domain, and wherein the resistancedomain includes a polymer material with a high oxygen solubility.

In an aspect of the first embodiment, the resistance domain includes apolymer material selected from the group consisting of silicone,fluorocarbon, and perfluorocarbon.

In an aspect of the first embodiment, the sensor further includes a cellimpermeable domain that is substantially impermeable to cells, whereinthe cell impermeable domain is located more distal to the workingelectrode than the enzyme domain, and wherein the cell impermeabledomain includes a polymer material with a high oxygen solubility.

In an aspect of the first embodiment, the cell impermeable domainincludes a polymer material selected from the group consisting ofsilicone, fluorocarbon, and perfluorocarbon.

In an aspect of the first embodiment, the sensor further includes a celldisruptive domain that includes a substantially porous structure,wherein the cell disruptive domain is located more distal to the workingelectrode than the enzyme domain, and wherein the cell disruptive domainincludes a polymer material with high oxygen solubility.

In an aspect of the first embodiment, the cell impermeable domainincludes a polymer material selected from the group consisting ofsilicone, fluorocarbon, and perfluorocarbon.

In an aspect of the first embodiment, the sensor further includes aninterference domain configured to limit or block interfering species,wherein the interference domain is located more proximal to the workingelectrode than the enzyme domain, and wherein the interference domainincludes a polymer material with a high oxygen solubility.

In an aspect of the first embodiment, the interference domain includes apolymer material selected from the group consisting of silicone,fluorocarbon, and perfluorocarbon.

In an aspect of the first embodiment, the sensor further includes anelectrolyte domain configured to provide hydrophilicity at the workingelectrode, wherein the electrolyte domain is located more proximal tothe working electrode than the enzyme domain, and wherein theelectrolyte domain includes a polymer material with a high oxygensolubility.

In an aspect of the first embodiment, the electrolyte domain includes apolymer material selected from the group consisting of silicone,fluorocarbon, and perfluorocarbon.

In a second embodiment, an analyte sensing device configured forimplantation into a tissue of a host is provided, the device includingan oxygen-utilizing source; a membrane system configured to provide atleast one function selected from the group consisting of protection ofthe device from a biological environment; diffusion resistance of ananalyte; a catalyst for enabling an enzymatic reaction; and limitationof interfering species; wherein the membrane system includes a polymermaterial with a high oxygen solubility, wherein the membrane system isadjacent to the oxygen-utilizing source.

In an aspect of the second embodiment, the oxygen-utilizing sourceincludes an enzyme.

In an aspect of the second embodiment, the membrane system includes thepolymer material with the high oxygen solubility, wherein the polymermaterial is substantially continuously situated between the enzyme andthe tissue.

In an aspect of the second embodiment, the oxygen-utilizing sourceincludes an electroactive surface.

In an aspect of the second embodiment, the membrane system includes thepolymer material with the high oxygen solubility, wherein the polymermaterial is substantially continuously situated between theelectroactive surface and the tissue.

In an aspect of the second embodiment, the oxygen-utilizing sourceincludes cells.

In an aspect of the second embodiment, the membrane system includes thepolymer material with the high oxygen solubility, wherein the polymermaterial is substantially continuously situated between the cells andthe tissue.

In an aspect of the second embodiment, the polymer material is selectedfrom the group consisting of silicone, fluorocarbon, andperfluorocarbon.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exploded perspective view of an implantable glucose sensorin one exemplary embodiment.

FIG. 2 is a block diagram that illustrates the sensor electronics in oneembodiment; however a variety of sensor electronics configurations canbe implemented with the preferred embodiments.

FIG. 3 is a graph that shows a raw data stream obtained from a glucosesensor over a 36-hour time span in one example.

FIG. 4 is a schematic illustration of a membrane system of the device ofFIG. 1.

FIG. 5A is a schematic diagram of oxygen concentration profiles througha prior art membrane.

FIG. 5B is a schematic diagram of oxygen concentration profiles throughthe membrane system of the preferred embodiments.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the present invention.

DEFINITIONS

In order to facilitate an understanding of the preferred embodiments, anumber of terms are defined below.

The term “analyte” as used herein is a broad term and is used in itsordinary sense, including, without limitation, to refer to a substanceor chemical constituent in a biological fluid (for example, blood,interstitial fluid, cerebral spinal fluid, lymph fluid or urine) thatcan be analyzed. Analytes can include naturally occurring substances,artificial substances, metabolites, and/or reaction products. In someembodiments, the analyte for measurement by the sensing regions,devices, and methods is glucose. However, other analytes arecontemplated as well, including but not limited to acarboxyprothrombin;acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase;albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactiveprotein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholicacid; chloroquine; cholesterol; cholinesterase; conjugated 1-βhydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MMisoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine;dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcoholdehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Beckermuscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A,hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F,D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1,Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax,sexual differentiation, 21-deoxycortisol); desbutylhalofantrine;dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocytearginase; erythrocyte protoporphyrin; esterase D; fattyacids/acylglycines; free β-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins and hormones naturally occurring in blood or interstitialfluids can also constitute analytes in certain embodiments. The analytecan be naturally present in the biological fluid or endogenous, forexample, a metabolic product, a hormone, an antigen, an antibody, andthe like. Alternatively, the analyte can be introduced into the body orexogenous, for example, a contrast agent for imaging, a radioisotope, achemical agent, a fluorocarbon-based synthetic blood, or a drug orpharmaceutical composition, including but not limited to insulin;ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants(nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons,hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines,methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil,Sandrex, Plegine); depressants (barbituates, methaqualone, tranquilizerssuch as Valium, Librium, Miltown, Serax, Equanil, Tranxene);hallucinogens (phencyclidine, lysergic acid, mescaline, peyote,psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine,Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil);designer drugs (analogs of fentanyl, meperidine, amphetamines,methamphetamines, and phencyclidine, for example, Ecstasy); anabolicsteroids; and nicotine. The metabolic products of drugs andpharmaceutical compositions are also contemplated analytes. Analytessuch as neurochemicals and other chemicals generated within the body canalso be analyzed, such as, for example, ascorbic acid, uric acid,dopamine, noradrenaline, 3-methoxytyramine (3MT),3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA),5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid (FHIAA).

The terms “operable connection,” “operably connected,” and “operablylinked” as used herein are broad terms and are used in their ordinarysense, including, without limitation, one or more components linked toanother component(s) in a manner that allows transmission of signalsbetween the components. For example, one or more electrodes can be usedto detect the amount of analyte in a sample and convert that informationinto a signal; the signal can then be transmitted to a circuit. In thiscase, the electrode is “operably linked” to the electronic circuitry.

The term “host” as used herein is a broad term and is used in itsordinary sense, including, without limitation, mammals, particularlyhumans.

The terms “electrochemically reactive surface” and “electroactivesurface” as used herein are broad terms and are used in their ordinarysense, including, without limitation, the surface of an electrode wherean electrochemical reaction takes place. As one example, a workingelectrode measures hydrogen peroxide produced by the enzyme catalyzedreaction of the analyte being detected reacts creating an electriccurrent (for example, detection of glucose analyte utilizing glucoseoxidase produces H₂O₂ as a by product, H₂O₂ reacts with the surface ofthe working electrode producing two protons (2H⁺), two electrons (2e⁻)and one molecule of oxygen (O₂) which produces the electronic currentbeing detected). In the case of the counter electrode, a reduciblespecies, for example, O₂ is reduced at the electrode surface in order tobalance the current being generated by the working electrode.

The term “sensing region” as used herein is a broad term and is used inits ordinary sense, including, without limitation, the region of amonitoring device responsible for the detection of a particular analyte.The sensing region generally comprises a non-conductive body, a workingelectrode, a reference electrode, and/or a counter electrode (optional)passing through and secured within the body forming electrochemicallyreactive surfaces on the body, an electronic connective means at anotherlocation on the body, and a multi-domain membrane affixed to the bodyand covering the electrochemically reactive surface.

The terms “raw data stream” and “data stream,” as used herein, are broadterms and are used in their ordinary sense, including, withoutlimitation, an analog or digital signal directly related to the measuredglucose concentration from the glucose sensor. In one example, the rawdata stream is digital data in “counts” converted by an A/D converterfrom an analog signal (for example, voltage or amps) representative of aglucose concentration. The terms broadly encompass a plurality of timespaced data points from a substantially continuous glucose sensor, whichcomprises individual measurements taken at time intervals ranging fromfractions of a second up to, for example, 1, 2, or 5 minutes or longer.

The term “counts,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, a unit of measurement ofa digital signal. In one example, a raw data stream measured in countsis directly related to a voltage (for example, converted by an A/Dconverter), which is directly related to current from the workingelectrode. In another example, counter electrode voltage measured incounts is directly related to a voltage.

The term “electrical potential,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, theelectrical potential difference between two points in a circuit which isthe cause of the flow of a current.

The term “ischemia,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, local and temporarydeficiency of blood supply due to obstruction of circulation to a part(for example, sensor). Ischemia can be caused by mechanical obstruction(for example, arterial narrowing or disruption) of the blood supply, forexample.

The term “system noise,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, unwanted electronicor diffusion-related noise which can include Gaussian, motion-related,flicker, kinetic, or other white noise, for example.

The terms “signal artifacts” and “transient non-glucose related signalartifacts,” as used herein, are broad terms and are used in theirordinary sense, including, without limitation, signal noise that iscaused by substantially non-glucose reaction rate-limiting phenomena,such as ischemia, pH changes, temperature changes, pressure, and stress,for example. Signal artifacts, as described herein, are typicallytransient and are characterized by higher amplitude than system noise.

The terms “low noise,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, noise thatsubstantially decreases signal amplitude.

The terms “high noise” and “high spikes,” as used herein, are broadterms and are used in their ordinary sense, including, withoutlimitation, noise that substantially increases signal amplitude.

The term “silicone composition” as used herein is a broad term and isused in its ordinary sense, including, without limitation, a compositionof matter that comprises polymers having at least silicon and oxygenatoms in the backbone.

The phrase “distal to” as used herein is a broad term and is used in itsordinary sense, including, without limitation, the spatial relationshipbetween various elements in comparison to a particular point ofreference. For example, some embodiments of a device include a membranesystem having a cell disruptive domain and a cell impermeable domain. Ifthe sensor is deemed to be the point of reference and the celldisruptive domain is positioned farther from the sensor, then thatdomain is distal to the sensor.

The phrase “proximal to” as used herein is a broad term and is used inits ordinary sense, including, without limitation, the spatialrelationship between various elements in comparison to a particularpoint of reference. For example, some embodiments of a device include amembrane system having a cell disruptive domain and a cell impermeabledomain. If the sensor is deemed to be the point of reference and thecell impermeable domain is positioned nearer to the sensor, then thatdomain is proximal to the sensor.

The terms “interferants” and “interfering species,” as used herein, arebroad terms and are used in their ordinary sense, including, but notlimited to, effects and/or species that interfere with the measurementof an analyte of interest in a sensor to produce a signal that does notaccurately represent the analyte measurement. In an electrochemicalsensor, interfering species can include compounds with an oxidationpotential that overlaps with that of the analyte to be measured.

As employed herein, the following abbreviations apply: Eq and Eqs(equivalents); mEq (milliequivalents); M (molar); mM (millimolar) μM(micromolar); N (Normal); mol (moles); mmol (millimoles); μmol(micromoles); nmol (nanomoles); g (grams); mg (milligrams); μg(micrograms); Kg (kilograms); L (liters); mL (milliliters); dL(deciliters); μL (microliters); cm (centimeters); mm (millimeters); μm(micrometers); nm (nanometers); h and hr (hours); min. (minutes); s andsec. (seconds); ° C. (degrees Centigrade).

Overview

Membrane systems of the preferred embodiments are suitable for use withimplantable devices in contact with a biological fluid. For example, themembrane systems can be utilized with implantable devices such asdevices for monitoring and determining analyte levels in a biologicalfluid, for example, glucose levels for individuals having diabetes. Insome embodiments, the analyte-measuring device is a continuous device.Alternatively, the device can analyze a plurality of intermittentbiological samples. The analyte-measuring device can use any method ofanalyte-measurement, including enzymatic, chemical, physical,electrochemical, spectrophotometric, polarimetric, calorimetric,radiometric, or the like.

Although some of the description that follows is directed atglucose-measuring devices, including the described membrane systems andmethods for their use, these membrane systems are not limited to use indevices that measure or monitor glucose. These membrane systems aresuitable for use in a variety of devices, including, for example, thosethat detect and quantify other analytes present in biological fluids(including, but not limited to, cholesterol, amino acids, alcohol,galactose, and lactate), cell transplantation devices (see, for example,U.S. Pat. Nos. 6,015,572, 5,964,745, and 6,083,523), drug deliverydevices (see, for example, U.S. Pat. Nos. 5,458,631, 5,820,589, and5,972,369), and the like. Preferably, implantable devices that includethe membrane systems of the preferred embodiments are implanted in softtissue, for example, abdominal, subcutaneous, and peritoneal tissues,the brain, the intramedullary space, and other suitable organs or bodytissues.

In addition to the glucose-measuring device described below, themembrane systems of the preferred embodiments can be employed with avariety of known glucose measuring-devices. In some embodiments, theelectrode system can be used with any of a variety of known in vivoanalyte sensors or monitors, such as U.S. Pat. No. 6,001,067 to Shultset al.; U.S. Pat. No. 6,702,857 to Brauker et al.; U.S. Pat. No.6,212,416 to Ward et al.; U.S. Pat. No. 6,119,028 to Schulman et al.;U.S. Pat. No. 6,400,974 to Lesho; U.S. Pat. No. 6,595,919 to Berner etal.; U.S. Pat. No. 6,141,573 to Kurnik et al.; U.S. Pat. No. 6,122,536to Sun et al.; European Patent Application EP 1153571 to Varall et al.;U.S. Pat. No. 6,512,939 to Colvin et al.; U.S. Pat. No. 5,605,152 toSlate et al.; U.S. Pat. No. 4,431,004 to Bessman et al.; U.S. Pat. No.4,703,756 to Gough et al.; U.S. Pat. No. 6,514,718 to Heller et al.;U.S. Pat. No. 5,985,129 to Gough et al.; WO Patent ApplicationPublication No. 04/021877 to Caduff; U.S. Pat. No. 5,494,562 to Maley etal.; U.S. Pat. No. 6,120,676 to Heller et al.; and U.S. Pat. No.6,542,765 to Guy et al., each of which are incorporated in thereentirety herein by reference. In general, it is understood that thedisclosed embodiments are applicable to a variety of continuous glucosemeasuring device configurations.

FIG. 1 is an exploded perspective view of one exemplary embodimentcomprising an implantable glucose sensor 10 that utilizes amperometricelectrochemical sensor technology to measure glucose. In this exemplaryembodiment, a body 12 with a sensing region 14 includes an electrodesystem 16 and sensor electronics, which are described in more detailwith reference to FIG. 2.

In this embodiment, the electrode system 16 is operably connected to thesensor electronics (FIG. 2) and includes electroactive surfaces, whichare covered by a membrane system 18. The membrane system 18 is disposedover the electroactive surfaces of the electrode system 16 and providesone or more of the following functions: 1) protection of the exposedelectrode surface from the biological environment (cell impermeabledomain); 2) diffusion resistance (limitation) of the analyte (resistancedomain); 3) a catalyst for enabling an enzymatic reaction (enzymedomain); 4) limitation or blocking of interfering species (interferencedomain); and/or 5) hydrophilicity at the electrochemically reactivesurfaces of the sensor interface (electrolyte domain), for example, asdescribed in co-pending U.S. patent application Ser. No. 10/838,912,filed May 3, 2004 and entitled “IMPLANTABLE ANALYTE SENSOR,” thecontents of which are hereby incorporated herein by reference in theirentirety. The membrane system can be attached to the sensor body 12 bymechanical or chemical methods such as are described in co-pending U.S.patent application MEMBRANE ATTACHMENT and U.S. patent application Ser.No. 10/838,912 filed May 3, 2004 and entitled, “IMPLANTABLE ANALYTESENSOR”, the contents of which are hereby incorporated herein byreference in their entirety.

The membrane system 18 of the preferred embodiments, which are describedin more detail below with reference to FIGS. 4 and 5, is formed at leastpartially from materials with high oxygen solubility. These materialsact as a high oxygen soluble domain, dynamically retaining a highavailability of oxygen that can be used to compensate for the localoxygen deficit during times of transient ischemia, which is described inmore detail below and with reference to FIG. 3. As a result, themembrane systems of the preferred embodiments enable glucose sensors andother implantable devices such as cell transplantation devices tofunction in the subcutaneous space even during local transient ischemia.

In some embodiments, the electrode system 16, which is located on orwithin the sensing region 14, is comprised of at least a working and areference electrode with an insulating material disposed therebetween.In some alternative embodiments, additional electrodes can be includedwithin the electrode system, for example, a three-electrode system(working, reference, and counter electrodes) and/or including anadditional working electrode (which can be used to generate oxygen,measure an additional analyte, or can be configured as a baselinesubtracting electrode, for example).

In the exemplary embodiment of FIG. 1, the electrode system includesthree electrodes (working, counter, and reference electrodes), whereinthe counter electrode is provided to balance the current generated bythe species being measured at the working electrode. In the case of aglucose oxidase based glucose sensor, the species being measured at theworking electrode is H₂O₂. Glucose oxidase, GOX, catalyzes theconversion of oxygen and glucose to hydrogen peroxide and gluconateaccording to the following reaction:

GOX+Glucose+O₂→Gluconate+H₂O₂+reduced GOX

The change in H₂O₂ can be monitored to determine glucose concentrationbecause for each glucose molecule metabolized, there is a proportionalchange in the product H₂O₂. Oxidation of H₂O₂ by the working electrodeis balanced by reduction of ambient oxygen, enzyme generated H₂O₂, orother reducible species at the counter electrode. The H₂O₂ produced fromthe glucose oxidase reaction further reacts at the surface of workingelectrode and produces two protons (2H+), two electrons (2e−), and oneoxygen molecule (O2). In such embodiments, because the counter electrodeutilizes oxygen as an electron acceptor, the most likely reduciblespecies for this system are oxygen or enzyme generated peroxide. Thereare two main pathways by which oxygen can be consumed at the counterelectrode. These pathways include a four-electron pathway to producehydroxide and a two-electron pathway to produce hydrogen peroxide. Inaddition to the counter electrode, oxygen is further consumed by thereduced glucose oxidase within the enzyme domain. Therefore, due to theoxygen consumption by both the enzyme and the counter electrode, thereis a net consumption of oxygen within the electrode system.Theoretically, in the domain of the working electrode there issignificantly less net loss of oxygen than in the region of the counterelectrode. In addition, there is a close correlation between the abilityof the counter electrode to maintain current balance and sensorfunction.

In general, in electrochemical sensors wherein an enzymatic reactiondepends on oxygen as a co-reactant, depressed function or inaccuracy canbe experienced in low oxygen environments, for example in vivo.Subcutaneously implanted devices are especially susceptible to transientischemia that can compromise device function; for example, because ofthe enzymatic reaction required for an implantable amperometric glucosesensor, oxygen must be in excess over glucose in order for the sensor toeffectively function as a glucose sensor. If glucose becomes in excess,the sensor turns into an oxygen sensitive device. In vivo, glucoseconcentration can vary from about one hundred times or more that of theoxygen concentration. Consequently, oxygen becomes a limiting reactantin the electrochemical reaction and when insufficient oxygen is providedto the sensor, the sensor is unable to accurately measure glucoseconcentration. Those skilled in the art interpret oxygen limitationsresulting in depressed function or inaccuracy as a problem ofavailability of oxygen to the enzyme and/or counter electrode. Oxygenlimitations can also be seen during periods of transient ischemia thatoccur, for example, under certain postures or when the region around theimplanted sensor is compressed so that blood is forced out of thecapillaries. Such ischemic periods observed in implanted sensors canlast for many minutes or even an hour or longer.

FIG. 2 is a block diagram that illustrates sensor electronics in oneexemplary embodiment; one skilled in the art appreciates, however, avariety of sensor electronics configurations can be implemented with thepreferred embodiments. In this embodiment, a potentiostat 20 is shown,which is operatively connected to electrode system 16 (FIG. 1) to obtaina current value, and includes a resistor (not shown) that translates thecurrent into voltage. The A/D converter 21 digitizes the analog signalinto “counts” for processing. Accordingly, the resulting raw data signalin counts is directly related to the current measured by thepotentiostat.

A microprocessor 22 is the central control unit that houses EEPROM 23and SRAM 24, and controls the processing of the sensor electronics. Thealternative embodiments can utilize a computer system other than amicroprocessor to process data as described herein. In some alternativeembodiments, an application-specific integrated circuit (ASIC) can beused for some or all the sensor's central processing. EEPROM 23 providessemi-permanent storage of data, storing data such as sensor ID andprogramming to process data signals (for example, programming for datasmoothing such as described elsewhere herein). SRAM 24 is used for thesystem's cache memory, for example for temporarily storing recent sensordata.

The battery 25 is operatively connected to the microprocessor 22 andprovides the power for the sensor. In one embodiment, the battery is aLithium Manganese Dioxide battery, however any appropriately sized andpowered battery can be used. In some embodiments, a plurality ofbatteries can be used to power the system. Quartz Crystal 26 isoperatively connected to the microprocessor 22 and maintains system timefor the computer system.

The RF Transceiver 27 is operably connected to the microprocessor 22 andtransmits the sensor data from the sensor to a receiver. Although a RFtransceiver is shown here, some other embodiments can include a wiredrather than wireless connection to the receiver. In yet otherembodiments, the sensor can be transcutaneously connected via aninductive coupling, for example. The quartz crystal 28 provides thesystem time for synchronizing the data transmissions from the RFtransceiver. The transceiver 27 can be substituted with a transmitter inone embodiment.

Although FIGS. 1 to 2 and associated text illustrate and describe oneexemplary embodiment of an implantable glucose sensor, the electrodesystem, electronics and its method of manufacture of the preferredembodiments described below can be implemented on any knownelectrochemical sensor, including those described in co-pending U.S.patent application Ser. No. 10/838,912 filed May 3, 2004 and entitled,“IMPLANTABLE ANALYTE SENSOR”; U.S. patent application Ser. No.10/789,359 filed Feb. 26, 2004 and entitled, “INTEGRATED DELIVERY DEVICEFOR A CONTINUOUS GLUCOSE SENSOR”; “OPTIMIZED SENSOR GEOMETRY FOR ANIMPLANTABLE GLUCOSE SENSOR”; U.S. application Ser. No. 10/633,367 filedAug. 1, 2003 entitled, “SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSORDATA”, the contents of each of which are hereby incorporated byreference in their entireties.

FIG. 3 is a graph that shows a raw data stream obtained from a glucosesensor with a conventional membrane system. The x-axis represents timein minutes. The y-axis represents sensor data in counts. In thisexample, sensor output in counts is transmitted every 30 seconds. Theraw data stream 30 includes substantially smooth sensor output in someportions, however other portions exhibit transient non-glucose relatedsignal artifacts 32.

The raw data stream 30 includes substantially smooth sensor output insome portions, however other portions exhibit erroneous or transientnon-glucose related signal artifacts 32. Particularly, referring to thesignal artifacts 32, it is believed that effects of local ischemia onprior art electrochemical sensors creates erroneous (non-glucose) signalvalues due to oxygen deficiencies either at the enzyme within themembrane system and/or at the counter electrode on the electrodesurface.

In one situation, when oxygen is deficient relative to the amount ofglucose, the enzymatic reaction is limited by oxygen rather thanglucose. Thus, the output signal is indicative of the oxygenconcentration rather than the glucose concentration, producing erroneoussignals. Additionally, when an enzymatic reaction is rate-limited byoxygen, glucose is expected to build up in the membrane because it isnot completely catabolized during the oxygen deficit. When oxygen isagain in excess, there is also excess glucose due to the transientoxygen deficit. The enzyme rate then speeds up for a short period untilthe excess glucose is catabolized, resulting in spikes of non-glucoserelated increased sensor output. Accordingly, because excess oxygen(relative to glucose) is necessary for proper sensor function, transientischemia can result in a loss of signal gain in the sensor data.

In another situation, oxygen deficiency can be seen at the counterelectrode when insufficient oxygen is available for reduction, whichthus affects the counter electrode in that it is unable to balance thecurrent coming from the working electrode. When insufficient oxygen isavailable for the counter electrode, the counter electrode can be drivenin its electrochemical search for electrons all the way to its mostnegative value, which can be ground, or 0.0 V, which causes thereference to shift, reducing the bias voltage such as is described inmore detail below. In other words, a common result of ischemia is seenas a drop off in sensor current as a function of glucose concentration(for example, lower sensitivity). This occurs because the workingelectrode no longer oxidizes all of the H₂O₂ arriving at its surfacebecause of the reduced bias. In some extreme circumstances, an increasein glucose can produce no increase in current or even a decrease incurrent.

In some situations, transient ischemia can occur at high glucose levels,wherein oxygen can become limiting to the enzymatic reaction, resultingin a non-glucose dependent downward trend in the data. In somesituations, certain movements or postures taken by the patient can causetransient signal artifacts as blood is squeezed out of the capillaries,resulting in local ischemia, and causing non-glucose dependent signalartifacts. In some situations, oxygen can also become transientlylimited due to contracture of tissues around the sensor interface. Thisis similar to the blanching of skin that can be observed when one putspressure on it. Under such pressure, transient ischemia can occur inboth the epidermis and subcutaneous tissue. Transient ischemia is commonand well tolerated by subcutaneous tissue. However, such ischemicperiods can cause an oxygen deficit in implanted devices that can lastfor many minutes or even an hour or longer.

Although some examples of the effects of transient ischemia on a priorart glucose sensor are described above, similar effects can be seen withanalyte sensors that use alternative catalysts to detect other analytes,for example, amino acids (amino acid oxidase), alcohol (alcoholoxidase), galactose (galactose oxidase), lactate (lactate oxidase), andcholesterol (cholesterol oxidase), or the like.

Membrane Systems of the Preferred Embodiments

In order to overcome the effects of transient ischemia, the membranesystems 18 of the preferred embodiments include materials with highoxygen solubility. These materials increase the local amount of oxygento aid in compensating for local oxygen deficits during ischemicconditions. As a result, the membrane systems of the preferredembodiments enable analyte sensors and other devices such as celltransplantation devices to function in the subcutaneous space evenduring local transient ischemia.

The phrases “high oxygen solubility” and “high oxygen soluble” as usedherein are broad phrases and are used in their ordinary sense,including, without limitation, a domain or material property thatincludes higher oxygen solubility than aqueous media so that itconcentrates oxygen from the biological fluid surrounding the membranesystem. In some preferred embodiments, a high oxygen solubility polymerhas at least about 3× higher oxygen solubility than aqueous media, morepreferably at least about 4×, 5×, or 6× higher oxygen solubility thanaqueous media, and most preferably at least about 7×, 8×, 9×, 10× ormore higher oxygen solubility than aqueous media. In one embodiment,high oxygen solubility is defined as having higher oxygen solubilitythan at least one of a hydrocarbonaceous polymer and an oxyhydrocarbonpolymer (a hydrocarbonaceous polymer is a polymeric material consistingof carbon and hydrogen atoms and an oxyhydrocarbonaceous polymer is apolymeric material consisting of carbon, hydrogen, and oxygen atoms).Oxygen solubility can be measured using any known technique, for exampleby removing the oxygen from the polymer (namely, solution) via at leastthree Freeze-Pump-Thaw cycles and then measuring the resultant oxygen(for example, using a manometer).

Oxygen permeability (Dk) is calculated as diffusion multiplied bysolubility. Oxygen Permeability is conveniently reported in units ofBarrers (1 Barrer=10⁻¹⁰ cm³ O₂ (STP) cm/cm²s cmHg). Insulating materialsof preferred embodiments that have a high oxygen permeability typicallyhave an oxygen permeability of from about 1 Barrer or less to about 1000Barrers or more, preferably from about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or100 Barrers to about 125, 150, 175, 200, 225, 250, 275, 300, 325, 350,375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, or950 Barrers.

In one exemplary embodiment, the properties of silicone (and/or siliconecompositions) inherently enable materials formed from silicone to act asa high oxygen solubility domain. Utilization of a high oxygen solublematerial in an electrochemical sensor is advantageous because it isbelieved to dynamically retain high oxygen availability tooxygen-utilizing sources (for example, an enzyme and/or a counterelectrode of an electrochemical cell).

As described below with reference to FIG. 4, the membrane system 18 caninclude two or more domains that cover an implantable device, forexample, an implantable glucose sensor. In the example of an implantableenzyme-based electrochemical glucose sensor, the membrane preventsdirect contact of the biological fluid sample with the electrodes, whilecontrolling the permeability of selected substances (for example, oxygenand glucose) present in the biological fluid through the membrane forreaction in an enzyme rich domain with subsequent electrochemicalreaction of formed products at the electrodes.

The membrane systems of preferred embodiments are constructed of two ormore domains. The multi-domain membrane can be formed from one or moredistinct layers and can comprise the same or different materials. Theterm “domain” is a broad term and is used in its ordinary sense,including, without limitation, a single homogeneous layer or region thatincorporates the combined functions one or more domains, or a pluralityof layers or regions that each provide one or more of the functions ofeach of the various domains.

FIG. 4 is an illustration of a membrane system in one preferredembodiment. The membrane system 18 can be used with a glucose sensorsuch, as is described above with reference to FIG. 1. In thisembodiment, the membrane system 18 includes a cell disruptive domain 40most distal of all domains from the electrochemically reactive surfaces,a cell impermeable domain 42 less distal from the electrochemicallyreactive surfaces than the cell disruptive domain, a resistance domain44 less distal from the electrochemically reactive surfaces than thecell impermeable domain, an enzyme domain 46 less distal from theelectrochemically reactive surfaces than the resistance domain, aninterference domain 48 less distal from the electrochemically reactivesurfaces than the enzyme domain, and an electrolyte domain 50 adjacentto the electrochemically reactive surfaces. However, it is understoodthat the membrane system can be modified for use in other devices, byincluding only two or more of the domains, or additional domains notrecited above.

In some embodiments, the membrane system is formed as a homogeneousmembrane, namely, a membrane having substantially uniformcharacteristics from one side of the membrane to the other. However, amembrane can have heterogeneous structural domains, for example, domainsresulting from the use of block copolymers (for example, polymers inwhich different blocks of identical monomer units alternate with eachother), but can be defined as homogeneous overall in that each of theabove-described domains functions by the preferential diffusion of somesubstance through the homogeneous membrane.

In the preferred embodiments, one or more of the above-described domainsare formed from high oxygen solubility material. Utilization of highoxygen solubility material is advantageous because it is believed todynamically retain a higher amount of oxygen, which maintains higheroxygen availability to selected locations (for example, the enzymeand/or counter electrode). In some embodiments, the high oxygen solublematerial includes silicones, fluorocarbons, perfluorocarbons, or thelike. In one embodiment, one or more domains is/are formed from asilicone composition that allows the transport of glucose other suchwater-soluble molecules (for example, drugs), such as are described inmore detail with reference to co-pending U.S. application Ser. No.10/685,636 filed Oct. 28, 2003 and entitled, “SILICONE COMPOSITION FORMEMBRANE SYSTEM,” the contents of which are hereby incorporated byreference in their entireties.

Cell Disruptive Domain

The cell disruptive domain 40 is positioned most distal to theimplantable device and is designed to support tissue ingrowth, todisrupt contractile forces typically found in a foreign body capsule, toencourage vascularity within the membrane, and/or to disrupt theformation of a barrier cell layer. In one embodiment, the celldisruptive domain 40 has an open-celled configuration withinterconnected cavities and solid portions, wherein the distribution ofthe solid portion and cavities of the cell disruptive domain includes asubstantially co-continuous solid domain and includes more than onecavity in three dimensions substantially throughout the entirety of thefirst domain. Cells can enter into the cavities; however they cannottravel through or wholly exist within the solid portions. The cavitiesallow most substances to pass through, including, for example, cells,and molecules. U.S. Pat. No. 6,702,857, filed Jul. 27, 2001, andentitled “MEMBRANE FOR USE WITH IMPLANTABLE DEVICES” and U.S. patentapplication Ser. No. 10/647,065, filed Aug. 22, 2003, and entitled,“POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES” describe membraneshaving a cell disruptive domain.

The cell disruptive domain 40 is preferably formed from high oxygensoluble materials such as polymers formed from silicone, fluorocarbons,perfluorocarbons, or the like. In one embodiment, the cell disruptivedomain is formed from a silicone composition with a non-siliconcontaining hydrophile such as such as polyethylene glycol, propyleneglycol, pyrrolidone, esters, amides, carbonates, or polypropylene glycolcovalently incorporated or grafted therein. In some alternativeembodiments, the cell disruptive domain is formed frompolyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polytetrafluoroethylene, polyurethanes,polypropylene (PP), polyvinylchloride (PVC), polyvinylidene fluoride(PVDF), polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA),polyether ether ketone (PEEK), polyurethanes, cellulosic polymers,polysulfones or block copolymers thereof including, for example,di-block, tri-block, alternating, random and graft copolymers.

In preferred embodiments, the thickness of the cell disruptive domain isfrom about 10 or less, 20, 30, 40, 50, 60, 70, 80, or 90 microns toabout 1500, 2000, 2500, or 3000 or more microns. In more preferredembodiments, the thickness of the cell disruptive domain is from about100, 150, 200 or 250 microns to about 1000, 1100, 1200, 1300, or 1400microns. In even more preferred embodiments, the thickness of the celldisruptive domain is from about 300, 350, 400, 450, 500, or 550 micronsto about 500, 550, 600, 650, 700, 750, 800, 850, or 900 microns.

The cell disruptive domain is optional and can be omitted when using animplantable device that does not prefer tissue ingrowth, for example, ashort-lived device (for example, less than one day to about a week) orone that delivers tissue response modifiers.

Cell Impermeable Domain

The cell impermeable domain 42 is positioned less distal to theimplantable device than the cell disruptive domain, and can be resistantto cellular attachment, impermeable to cells, and/or is composed of abiostable material. When the cell impermeable domain is resistant tocellular attachment (for example, attachment by inflammatory cells, suchas macrophages, which are therefore kept a sufficient distance fromother domains, for example, the enzyme domain), hypochlorite and otheroxidizing species are short-lived chemical species in vivo, andbiodegradation does not occur. Additionally, the materials preferred forforming this domain are resistant to the effects of these oxidativespecies and have thus been termed biodurable. See, for example, U.S.Pat. No. 6,702,857, filed Jul. 27, 2001, and entitled “MEMBRANE FOR USEWITH IMPLANTABLE DEVICES” and U.S. patent application Ser. No.10/647,065, filed Aug. 22, 2003, and entitled, “POROUS MEMBRANES FOR USEWITH IMPLANTABLE DEVICES.”

The cell impermeable domain 42 is preferably formed from high oxygensoluble materials such as polymers formed from silicone, fluorocarbons,perfluorocarbons, or the like. In one embodiment, the cell impermeabledomain is formed from a silicone composition with a hydrophile such assuch as polyethylene glycol, propylene glycol, pyrrolidone, esters,amides, carbonates, or polypropylene glycol covalently incorporated orgrafted therein. In some alternative embodiments, the cell impermeabledomain is formed from copolymers or blends of copolymers withhydrophilic polymers such as polyvinylpyrrolidone (PVP),polyhydroxyethyl methacrylate, polyvinylalcohol, polyacrylic acid,polyethers such as polyethylene glycol, and block copolymers thereof,including, for example, di-block, tri-block, alternating, random andgraft copolymers (block copolymers are discussed in U.S. Pat. Nos.4,803,243 and 4,686,044).

In preferred embodiments, the thickness of the cell impermeable domainis from about 10 or 15 microns or less to about 125, 150, 175, or 200microns or more. In more preferred embodiments, the thickness of thecell impermeable domain is from about 20, 25, 30, or 35 microns to about65, 70, 75, 80, 85, 90, 95, or 100 microns. In even more preferredembodiments, the cell impermeable domain is from about 40 or 45 micronsto about 50, 55, or 60 microns thick.

The cell disruptive domain 40 and cell impermeable domain 42 of themembrane system can be formed together as one unitary structure.Alternatively, the cell disruptive and cell impermeable domains 40, 42of the membrane system can be formed as two layers mechanically orchemically bonded together.

Resistance Domain

The resistance domain 44 is situated more proximal to the implantabledevice relative to the cell disruptive domain. The resistance domaincontrols the flux of oxygen and other analytes (for example, glucose) tothe underlying enzyme domain. As described in more detail elsewhereherein, there exists a molar excess of glucose relative to the amount ofoxygen in blood; that is, for every free oxygen molecule inextracellular fluid, there are typically more than 100 glucose moleculespresent (see Updike et al., Diabetes Care 5:207-21 (1982)). However, animmobilized enzyme-based sensor employing oxygen as cofactor is suppliedwith oxygen in non-rate-limiting excess in order to respond linearly tochanges in glucose concentration, while not responding to changes inoxygen tension. More specifically, when a glucose-monitoring reaction isoxygen-limited, linearity is not achieved above minimal concentrationsof glucose. Without a semipermeable membrane situated over the enzymedomain to control the flux of glucose and oxygen, a linear response toglucose levels can be obtained only up to about 40 mg/dL. However, in aclinical setting, a linear response to glucose levels is desirable up toat least about 500 mg/dL.

The resistance domain 44 includes a semipermeable membrane that controlsthe flux of oxygen and glucose to the underlying enzyme domain 46,preferably rendering oxygen in non-rate-limiting excess. As a result,the upper limit of linearity of glucose measurement is extended to amuch higher value than that which is achieved without the resistancedomain. In one embodiment, the resistance domain 44 exhibits anoxygen-to-glucose permeability ratio of approximately 200:1. As aresult, one-dimensional reactant diffusion is adequate to provide excessoxygen at all reasonable glucose and oxygen concentrations found in thesubcutaneous matrix (See Rhodes et al., Anal. Chem., 66:1520-1529(1994)). In some embodiments, a lower ratio of oxygen-to-glucose can besufficient to provide excess oxygen by using a high oxygen solubledomain (for example, a silicone material) to enhance thesupply/transport of oxygen to the enzyme membrane and/or electroactivesurfaces. By enhancing the oxygen supply through the use of a siliconecomposition, for example, glucose concentration can be less of alimiting factor. In other words, if more oxygen is supplied to theenzyme and/or electroactive surfaces, then more glucose can also besupplied to the enzyme without creating an oxygen rate-limiting excess.

The resistance domain 44 is preferably formed from high oxygen solublematerials such as polymers formed from silicone, fluorocarbons,perfluorocarbons, or the like. In one embodiment, the resistance domainis formed from a silicone composition with a hydrophile such as such aspolyethylene glycol, propylene glycol, pyrrolidone, esters, amides,carbonates, or polypropylene glycol covalently incorporated or graftedtherein. In some alternative embodiments, the resistance domain is frompolyurethane, for example, a polyurethaneurea/polyurethane-block-polyethylene glycol blend.

In some embodiments, the resistance domain 44 can be formed as a unitarystructure with the cell impermeable domain 42; that is, the inherentproperties of the resistance domain 44 can provide the functionalitydescribed with reference to the cell impermeable domain 42 such that thecell impermeable domain 42 is incorporated as a part of resistancedomain 44. In these embodiments, the combined resistance domain/cellimpermeable domain can be bonded to or formed as a skin on the celldisruptive domain 40 during a molding process such as described above.In another embodiment, the resistance domain 44 is formed as a distinctlayer and chemically or mechanically bonded to the cell disruptivedomain 40 (if applicable) or the cell impermeable domain 42 (when theresistance domain is distinct from the cell impermeable domain).

In preferred embodiments, the thickness of the resistance domain is fromabout 10 microns or less to about 200 microns or more. In more preferredembodiments, the thickness of the resistance domain is from about 15,20, 25, 30, or 35 microns to about 65, 70, 75, 80, 85, 90, 95, or 100microns. In more preferred embodiments, the thickness of the resistancedomain is from about 40 or 45 microns to about 50, 55, or 60 microns.

Enzyme Domain

An immobilized enzyme domain 46 is situated less distal from theelectrochemically reactive surfaces than the resistance domain 44. Inone embodiment, the immobilized enzyme domain 46 comprises glucoseoxidase. In other embodiments, the immobilized enzyme domain 46 can beimpregnated with other oxidases, for example, galactose oxidase,cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactateoxidase, or uricase. For example, for an enzyme-based electrochemicalglucose sensor to perform well, the sensor's response should neither belimited by enzyme activity nor cofactor concentration.

The enzyme domain 44 is preferably formed from high oxygen solublematerials such as polymers formed from silicone, fluorocarbons,perfluorocarbons, or the like. In one embodiment, the enzyme domain isformed from a silicone composition with a hydrophile such as such aspolyethylene glycol, propylene glycol, pyrrolidone, esters, amides,carbonates, or polypropylene glycol covalently incorporated or graftedtherein.

In one preferred embodiment, high oxygen solubility within the enzymedomain can be achieved by using a polymer matrix to host the enzymewithin the enzyme domain, which has a high solubility of oxygen. In oneexemplary embodiment of fluorocarbon-based polymers, the solubility ofoxygen within a perfluorocarbon-based polymer is 50-volume %. As areference, the solubility of oxygen in water is approximately 2-volume%.

Utilization of a high oxygen solubility material for the enzyme domainis advantageous because the oxygen dissolves more readily within thedomain and thereby acts as a high oxygen soluble domain optimizingoxygen availability to oxygen-utilizing sources (for example, the enzymeand/or counter electrode). When the resistance domain 44 and enzymedomain 46 both comprise a high oxygen soluble material, the chemicalbond between the enzyme domain 46 and resistance domain 44 can beoptimized, and the manufacturing made easy.

In preferred embodiments, the thickness of the enzyme domain is fromabout 1 micron or less to about 40, 50, 60, 70, 80, 90, or 100 micronsor more. In more preferred embodiments, the thickness of the enzymedomain is between about 1, 2, 3, 4, or 5 microns and 13, 14, 15, 20, 25,or 30 microns. In even more preferred embodiments, the thickness of theenzyme domain is from about 6, 7, or 8 microns to about 9, 10, 11, or 12microns.

Interference Domain

The interference domain 48 is situated less distal to the implantabledevice than the immobilized enzyme domain. Interferants are molecules orother species that are electro-reduced or electro-oxidized at theelectrochemically reactive surfaces, either directly or via an electrontransfer agent, to produce a false signal (for example, urate,ascorbate, or acetaminophen). In one embodiment, the interference domain48 prevents the penetration of one or more interferants into theelectrolyte phase around the electrochemically reactive surfaces.Preferably, this type of interference domain is much less permeable toone or more of the interferants than to the analyte.

In one embodiment, the interference domain 48 can include ioniccomponents incorporated into a polymeric matrix to reduce thepermeability of the interference domain to ionic interferants having thesame charge as the ionic components. In another embodiment, theinterference domain 48 includes a catalyst (for example, peroxidase) forcatalyzing a reaction that removes interferants. U.S. Pat. No. 6,413,396and U.S. Pat. No. 6,565,509 disclose methods and materials foreliminating interfering species; however in the preferred embodimentsany suitable method or material can be employed.

In another embodiment, the interference domain 48 includes a thinmembrane that is designed to limit diffusion of species, for example,those greater than 34 kD in molecular weight, for example. Theinterference domain permits analytes and other substances (for example,hydrogen peroxide) that are to be measured by the electrodes to passthrough, while preventing passage of other substances, such aspotentially interfering substances. In one embodiment, the interferencedomain 48 is constructed of polyurethane. In an alternative embodiment,the interference domain 48 comprises a high oxygen soluble polymer, suchas described above.

In preferred embodiments, the thickness of the interference domain isfrom about 0.1 microns or less to about 10 microns or more. In morepreferred embodiments, the thickness of the interference domain isbetween about 0.2, 0.3, 0.4, or 0.5 microns and about 5, 6, 7, 8, or 9microns. In more preferred embodiments, the thickness of theinterference domain is from about 0.6, 0.7, 0.8, 0.9, or 1 micron toabout 2, 3, or 4 microns.

Electrolyte Domain

An electrolyte domain 50 is situated more proximal to theelectrochemically reactive surfaces than the interference domain 48. Toensure the electrochemical reaction, the electrolyte domain 30 includesa semipermeable coating that maintains hydrophilicity at theelectrochemically reactive surfaces of the sensor interface. Theelectrolyte domain 50 enhances the stability of the interference domain48 by protecting and supporting the material that makes up theinterference domain. The electrolyte domain also 50 assists instabilizing the operation of the device by overcoming electrode start-upproblems and drifting problems caused by inadequate electrolyte. Thebuffered electrolyte solution contained in the electrolyte domain alsoprotects against pH-mediated damage that can result from the formationof a large pH gradient between the substantially hydrophobicinterference domain and the electrodes due to the electrochemicalactivity of the electrodes. In some embodiments, the electrolyte domainmay not be used, for example, when an interference domain is notprovided.

In one embodiment, the electrolyte domain 50 includes a flexible,water-swellable, substantially solid gel-like film having a “dry film”thickness of from about 2.5 microns to about 12.5 microns, morepreferably from about 3, 3.5, 4, 4.5, 5, or 5.5 to about 6, 6.5, 7, 7.5,8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 microns. “Dry film” thicknessrefers to the thickness of a cured film cast from a coating formulationonto the surface of the membrane by standard coating techniques.

In some embodiments, the electrolyte domain 50 is formed of a curablemixture of a urethane polymer and a hydrophilic polymer. Particularlypreferred coatings are formed of a polyurethane polymer having anioniccarboxylate functional groups and non-ionic hydrophilic polyethersegments, which is crosslinked in the presence of polyvinylpyrrolidoneand cured at a moderate temperature of about 50° C. In some preferredembodiments, the electrolyte domain 50 is formed from high oxygensoluble materials such as polymers formed from silicone, fluorocarbons,perfluorocarbons, or the like.

In one preferred embodiment, the electrolyte domain 50 is formed from ahigh oxygen soluble material, such as described above. In preferredembodiments, the thickness of the electrolyte domain is from about 1micron or less to about 40, 50, 60, 70, 80, 90, or 100 microns or more.In more preferred embodiments, the thickness of the electrolyte domainis from about 2, 3, 4, or 5 microns to about 15, 20, 25, or 30 microns.In even more preferred embodiments, the thickness of the electrolytedomain is from about 6, 7, or 8 microns to about 9, 10, 11, or 12microns.

Underlying the electrolyte domain is an electrolyte phase is afree-fluid phase including a solution containing at least one compound,typically a soluble chloride salt, which conducts electric current. Inone embodiment wherein the membrane system is used with a glucose sensorsuch as is described herein, the electrolyte phase flows over theelectrodes and is in contact with the electrolyte domain. The devices ofthe preferred embodiments contemplate the use of any suitableelectrolyte solution, including standard, commercially availablesolutions. Generally, the electrolyte phase can have the same osmoticpressure or a lower osmotic pressure than the sample being analyzed. Inpreferred embodiments, the electrolyte phase comprises normal saline.

In various embodiments, any of these domains can be omitted, altered,substituted for, and/or incorporated together without departing from thespirit of the preferred embodiments. For example, a distinct cellimpermeable domain may not exist. In such embodiments, other domainsaccomplish the function of the cell impermeable domain. As anotherexample, the interference domain can be eliminated in certainembodiments wherein two-electrode differential measurements are employedto eliminate interference, for example, one electrode being sensitive toglucose and electrooxidizable interferants and the other only tointerferants, such as is described in U.S. Pat. No. 6,514,718. In suchembodiments, the interference domain can be omitted.

A variety of configurations are contemplated with the membrane systemsof the preferred embodiments, however the exemplary configurations arenot meant to be limiting and may be modified within the scope of thepreferred embodiments. In one embodiment, the enzyme domain is formedfrom a material with a high oxygen solubility, which is believed tooptimize oxygen availability to the enzyme immobilized therein. Inanother embodiment, all domains between the fluid supply (for example,interstitial fluid) and the enzyme (up to and including the enzymedomain) are formed from a material with a high oxygen solubility, whichis believed to dynamically retain a substantially continuous path ofhigh oxygen availability to the enzyme and/or electroactive surfacesduring local ischemic periods. In yet another embodiment, all domains ofa membrane system are formed from high oxygen soluble materials; in thisway, the membrane system transports and/or maintains high oxygenavailability substantially continuously across the membrane system, fromthe interstitial fluid to the implantable device surface, providingincreased oxygen availability to the implantable device, for exampleelectroactive surfaces thereon or transplanted cells located therein.While not wishing to be bound by theory, it is believed that maintaininghigh oxygen availability at the interface of the implantable deviceimproves device performance even during transient ischemia and other lowoxygen situations.

Reference is now made to FIGS. 5A and 5B, which are schematic diagramsof oxygen concentration profiles through a prior art membrane (FIG. 5A)and a membrane system of the preferred embodiments (FIG. 5B). FIG. 5Aillustrates a fluid source 52, such as interstitial fluid within thesubcutaneous space, which provides fluid to a membrane system 54 a. Themembrane system 54 a is a conventional membrane, for example, formedfrom a polyurethane-based or other non-high oxygen soluble material. Anoxygen-utilizing source 56, such as the immobilized enzyme within theenzyme domain 46 or electroactive surfaces 16 described herein, utilizesoxygen from the fluid as a catalyst or in an electrochemical reaction.In some alternative embodiments, the oxygen-utilizing source 56comprises cells within a cell transplantation device, which utilizeoxygen in the fluid for cellular processes.

The upper dashed lines represent oxygen concentration in the fluidsource (C_(f)) and oxygen concentration in the membrane system (C_(m))at equilibrium (namely, without oxygen utilization) under normalconditions. However, when the membrane system 54 a interfaces with anoxygen-utilizing source 56, oxygen concentration within the membranesystem will be utilized. Accordingly, line 58 a represents oxygenconcentration under normal conditions decreasing at steady state as itpasses through the membrane system 54 a to the oxygen-utilizing source56. While not wishing to be bound by theory, the oxygen concentration atthe interface between the membrane system 54 a and the oxygen-utilizingsource 56 provides sufficient oxygen under normal conditions foroxygen-utilizing sources in vivo, such as enzymatic reactions, cellularprocesses, and electroactive surfaces.

Unfortunately, “normal conditions” do not always occur in vivo, forexample during transient ischemic periods, such as described in moredetail above with reference to FIG. 3. During “ischemic conditions,”oxygen concentration is decreased below normal to a concentration as lowas zero. Accordingly, line 60 a represents oxygen concentration duringan ischemic period, wherein the oxygen concentration of the fluid source(C_(f)) is approximately half of its normal concentration. A linearrelationship exists between the fluid source oxygen concentration(C_(f)) and the membrane system oxygen concentration (C_(m)) (seeHitchman, M. L. Measurement of Dissolved Oxygen. In Chemical Analysis;Elving, P., Winefordner, J., Eds.; John Wiley & Sons: New York, 1978;Vol. 49, pp. 63-70). Accordingly, line 62 a represents the oxygenconcentration within the membrane system during the ischemic period,which is approximately half of its normal concentration. Unfortunately,the resulting oxygen concentration at the interface of the membrane 54 aand oxygen-utilizing source 56 is approximately zero. While not wishingto bound by any particular theory, it is believed that the oxygenconcentration at the interface between the conventional membrane system54 a and the oxygen-utilizing source 56 does not provide sufficientoxygen for oxygen-utilizing sources in vivo, such as enzymaticreactions, cellular processes, and electroactive surfaces, during someischemic conditions.

Referring to FIG. 5B, a fluid source 52, such as interstitial fluidwithin the subcutaneous space, provides fluid to a membrane system 54 b.The membrane system 54 b is a membrane system of the preferredembodiments, such as an enzyme domain 46 or an entire membrane systemformed from a high oxygen soluble material such as described herein,through which the fluid passes. An oxygen-utilizing source 56, such asthe immobilized enzyme described herein, utilizes oxygen from the fluidas a catalyst. In some alternative embodiments, the oxygen-utilizingsource 56 comprises cells within a cell transplantation device, whichutilize oxygen in the fluid for cellular processes. In some alternativeembodiments, the oxygen-utilizing source 56 comprises an electroactivesurface that utilizes oxygen in an electrochemical reaction.

The upper dashed lines represent oxygen concentration in the fluidsource (C_(f)) and oxygen concentration in the membrane system (C_(m))at equilibrium (namely, without oxygen utilization) under normalconditions. The membrane system of the preferred embodiments 54 b isillustrated with a significantly higher oxygen concentration than theconventional membrane 54 a. This higher oxygen concentration atequilibrium is attributed to higher oxygen solubility inherent in theproperties of the membrane systems of the preferred embodiments ascompared to conventional membrane materials. Line 58 b represents oxygenconcentration under normal conditions decreasing at steady state as itpasses through the membrane system 54 b to the oxygen-utilizing source56. While not wishing to be bound by theory, the oxygen concentration atthe interface between the membrane system 54 b and the oxygen-utilizingsource 56 is believe to provide sufficient oxygen under normalconditions for oxygen-utilizing sources in vivo, such as enzymaticreactions, cellular processes, and electroactive surfaces.

Such as described above, “normal conditions” do not always occur invivo, for example during transient ischemic periods, wherein oxygenconcentration is decreased below normal to a concentration as low aszero. Accordingly, line 60 b represents oxygen concentration duringischemic conditions, wherein the oxygen concentration of the fluidsource (C_(f)) is approximately half of its normal concentration.Because of the linear relationship between the fluid source oxygenconcentration (C_(f)) and the membrane system oxygen concentration(C_(m)), the membrane system oxygen concentration, which is representedby a line 62 b, is approximately half of its normal concentration. Incontrast to the conventional membrane 62 a illustrated in FIG. 5A,however, the high oxygen solubility of the membrane system of thepreferred embodiments dynamically retains a higher oxygen availabilitywithin the membrane 54 b, which can be utilized during ischemic periodsto compensate for oxygen deficiency, illustrated by sufficient oxygenconcentration 62 b provided at the interface of the membrane 54 b andoxygen-utilizing source 56. Therefore, the high oxygen solubility of themembrane systems of the preferred embodiments enables device functioneven during transient ischemic periods.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in co-pending U.S.patent application Ser. No. 10/842,716, filed May 10, 2004 and entitled,“MEMBRANE SYSTEMS INCORPORATING BIOACTIVE AGENTS”; co-pending U.S.patent application Ser. No. 10/838,912 filed May 3, 2004 and entitled,“IMPLANTABLE ANALYTE SENSOR”; U.S. patent application Ser. No.10/789,359 filed Feb. 26, 2004 and entitled, “INTEGRATED DELIVERY DEVICEFOR A CONTINUOUS GLUCOSE SENSOR”; U.S. application Ser. No. 10/685,636filed Oct. 28, 2003 and entitled, “SILICONE COMPOSITION FOR MEMBRANESYSTEM”; U.S. application Ser. No. 10/648,849 filed Aug. 22, 2003 andentitled, “SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN AGLUCOSE SENSOR DATA STREAM”; U.S. application Ser. No. 10/646,333 filedAug. 22, 2003 entitled, “OPTIMIZED SENSOR GEOMETRY FOR AN IMPLANTABLEGLUCOSE SENSOR”; U.S. application Ser. No. 10/647,065 filed Aug. 22,2003 entitled, “POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES”; U.S.application Ser. No. 10/633,367 filed Aug. 1, 2003 entitled, “SYSTEM ANDMETHODS FOR PROCESSING ANALYTE SENSOR DATA”; U.S. Pat. No. 6,702,857entitled “MEMBRANE FOR USE WITH IMPLANTABLE DEVICES”; U.S. applicationSer. No. 09/916,711 filed Jul. 27, 2001 and entitled “SENSOR HEAD FORUSE WITH IMPLANTABLE DEVICE”; U.S. application Ser. No. 09/447,227 filedNov. 22, 1999 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTELEVELS”; U.S. application Ser. No. 10/153,356 filed May 22, 2002 andentitled “TECHNIQUES TO IMPROVE POLYURETHANE MEMBRANES FOR IMPLANTABLEGLUCOSE SENSORS”; U.S. application Ser. No. 09/489,588 filed Jan. 21,2000 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”;U.S. application Ser. No. 09/636,369 filed Aug. 11, 2000 and entitled“SYSTEMS AND METHODS FOR REMOTE MONITORING AND MODULATION OF MEDICALDEVICES”; and U.S. application Ser. No. 09/916,858 filed Jul. 27, 2001and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS,” as wellas issued patents including U.S. Pat. No. 6,001,067 issued Dec. 14, 1999and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S.Pat. No. 4,994,167 issued Feb. 19, 1991 and entitled “BIOLOGICAL FLUIDMEASURING DEVICE”; and U.S. Pat. No. 4,757,022 filed Jul. 12, 1988 andentitled “BIOLOGICAL FLUID MEASURING DEVICE”; U.S. Appl. No. 60/489,615filed Jul. 23, 2003 and entitled “ROLLED ELECTRODE ARRAY AND ITS METHODFOR MANUFACTURE”; U.S. Appl. No. 60/490,010 filed Jul. 25, 2003 andentitled “INCREASING BIAS FOR OXYGEN PRODUCTION IN AN ELECTRODEASSEMBLY”; U.S. Appl. No. 60/490,208 filed Jul. 25, 2003 and entitled“ELECTRODE ASSEMBLY WITH INCREASED OXYGEN GENERATION”; U.S. Appl. No.60/490,007 filed Jul. 25, 2003 and entitled “OXYGEN-GENERATING ELECTRODEFOR USE IN ELECTROCHEMICAL SENSORS”; U.S. application Ser. No.10/896,637 filed on Jul. 21, 2004 and entitled “ROLLED ELECTRODE ARRAYAND ITS METHOD FOR MANUFACTURE”; U.S. application Ser. No. 10/896,772filed on Jul. 21, 2004 and entitled “INCREASING BIAS FOR OXYGENPRODUCTION IN AN ELECTRODE ASSEMBLY”; U.S. application Ser. No.10/897,377 filed on Jul. 21, 2004 and entitled “ELECTRODE ASSEMBLY WITHINCREASED OXYGEN GENERATION”; U.S. application Ser. No. 10/897,312 filedon Jul. 21, 2004 and entitled “ELECTRODE SYSTEMS FOR ELECTROCHEMICALSENSORS”. The foregoing patent applications and patents are incorporatedherein by reference in their entireties.

All references cited herein are incorporated herein by reference intheir entireties. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that can varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention as embodied in the attached claims.

1-20. (canceled)
 21. A system for continuous in vivo measurement of aglucose concentration in a host, the system comprising: an implantablesensor configured to operatively connect with sensor electronics,wherein the sensor is configured to generate in vivo a signal indicativeof a concentration of glucose in a host; and a membrane located over thesensor, the membrane comprising: a first domain comprising an enzymeconfigured to catalyze a reaction that has glucose as a reactant; and asecond domain configured to control a flux therethrough of glucose tothe first domain, wherein the second domain comprises a material havingan oxygen permeability of from about 3 Barrers to about 1000 Barrers;sensor electronics configured to process the signal and determine aglucose concentration value.
 22. The implantable device of claim 21,wherein the material of the second domain has an oxygen permeability offrom about 5 Barrers to about 500 Barrers.
 23. The implantable device ofclaim 21, wherein the material of the second domain has an oxygenpermeability of from about 25 Barrers to about 250 Barrers.
 24. Theimplantable device of claim 21, wherein the membrane has a thickness offrom about 3 microns to about 100 microns.
 25. The implantable device ofclaim 21, wherein the membrane further comprises a third domainconfigured to limit or block passage of an interfering speciestherethrough.
 26. The implantable device of claim 21, wherein thematerial of the second domain comprises a copolymer comprisingpolyurethane and silicone.
 27. The implantable device of claim 21,wherein the material has an oxygen solubility that is at least aboutfour times greater than an oxygen solubility of water.
 28. Theimplantable device of claim 21, wherein the material has an oxygensolubility that is at least about five times greater than an oxygensolubility of water.
 29. The implantable device of claim 21, wherein thematerial has an oxygen solubility that is at least about six timesgreater than an oxygen solubility of water.
 30. The implantable deviceof claim 21, wherein the material has an oxygen solubility that is atleast about seven times greater than an oxygen solubility of water. 31.The implantable device of claim 21, wherein the material has an oxygensolubility that is at least about nine times greater than an oxygensolubility of water.
 32. The implantable device of claim 21, wherein thematerial has an oxygen solubility that is at least about ten timesgreater than an oxygen solubility of water.
 33. The implantable deviceof claim 21, wherein the material comprises a polyurethane polymer. 34.The implantable device of claim 21, wherein the polyurethane polymercomprises polyurethane urea.